tbuckley/cabot-search huggingface dataset:
Safety and tolerability of immune checkpoint inhibitor (CPI) use in advanced hepatocellular carcinoma (aHCC) with Child-Pugh (CP) class B and C.
Authors: Jennifer Brooke Valerin, Dalia Kaakour, Nataliya Mar, Elham Vosoughi
Journal: Journal of Clinical Oncology (2023)

e14676 Background: The vast majority of HCC cases occur in the setting of liver cirrhosis. Patients with decompensated cirrhosis CHILD-Pugh Class B and C (CPB and CPC) are usually excluded from clinical trials. Here we report the safety and tolerability of CPI in patients with CPB/CPC. Methods: A retrospective chart review was performed of all patients with aHCC who received therapy with CPI from 1/2019 to 12/2022 at our institution. Patients with CP class B and C were included in this study. Safety endpoints included rates of immune-related adverse events (irAEs), grade ≥3 adverse events (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]), duration of treatment with CPI and overall survival (OS) were reported. Results: We performed this retrospective chart review of 60 patients with aHCC who were treated with CPI at our institution. A total of 22 patients with CPB and CPC at the time of CPI initiation were included, 86.4% with CPB (n=19) and 13.6% with CPC (n=3). Median age was 68 (range 40-82). Amongst patients with CPB, 10 patients (45.4%) had CP score 7 (CP7) and 9 patients (40.9%) had CP score 8 or 9. Single agent nivolumab was the most common CPI used, followed by pembrolizumab and combination of ipilimumab and nivolumab, 38.4%, 27.3% and 13.6% respectively. Any grade irAEs were reported in 54.5% of patients (n=12).9% of patients (n=2) had grade ≥3 irAEs. In the CP7 subgroup, the rate of irAEs reported was 40% and no grade ≥3 irAEs were observed. In contrast, 55.5% of patients with CP 8 and 9 experienced irAEs and of those, 11.1% had grade ≥3 irAEs (n=1). In the CPC subgroup, 2 out of 3 patients reported irAEs (75%), one with a grade 4 irAE. GI complications(n=5) were the most common irAEs reported, followed by endocrine (n=4) and dermatologic complications (n=3). The median time on treatment was 1.63 months (95% CI,1.08-2.99). The median overall survival from the time of CPI initiation was 3.7 months (95% CI, 1.97-9.79). Conclusions: Immunotherapy has an acceptable safety and toxicity profile in aHCC patients with CP7. Higher rate of irAEs were observed in patients with CP ≥8. Further studies are warranted to evaluate the safety of CPI in patients with CP ≥8. We reported shorter duration of treatment with CPI and shorter OS in real world practice compared with those reported in the CheckMate 040 trial.[Table: see text]
Radiogenomics of muscle invasive bladder cancer.
Authors: Xingyu Chen, Touseef Qureshi, Yibin Xie, Simon Knott, Debiao Li, Charles Joel Rosser, Hideki Furuya
Journal: Journal of Clinical Oncology (2023)

e16587 Background: Accurate staging of Muscle Invasive Bladder Cancer (MIBC) is essential to ensure optimal treatment (e.g., radical cystectomy vs. bladder preservation). However, currently about 1/3 of patients are overstaged and 1/3 are understaged. There is a pressing need of accurate noninvasive staging for MIBC to assist clinical decision making. Methods: In this preliminary study, an extensive radiogenomic analysis of MIBC cases was performed to identify potential indicators of MIBC stages, and to automate the staging process. A total of 28 MRI scans and their matched transcriptomic profiles were obtained from subjects diagnosed with MIBC at different stages. In the genomics, a bulk RNA-seq from FFPE tissues was performed that identified 3 major clusters, high, intermediate, and low infiltrating immune cells and fibroblasts. This was followed by a bioinformatic analyses, such as pathway enrichment and gene set enrichment analyses, 15 most significant signatures were identified for stage categorization of MIBC (Fig. 1). In the radiomics, several hundred image-based features from bladder tumor in MRI were extracted and analyzed. The tumors were manually outlined and grouped into lower-stage (stage I and II) and higher-stage (stage III and IV) by the trained radiologists. Using various statistical tests, several radiomic features (e.g., heterogeneity, inverse contrast, entropy) were inferred as significant at discriminating the two groups (Fig. 2). A naïve Bayes machine learning model was then used to integrate such features and perform automated binary classification of cases into their true class. A 4-fold cross validation was performed in which a unique 75% and 25% of 28 cases were used for training and testing of the model respectively. Results: The model performance was assessed in terms of prediction (binary classification) of stages as mean sensitivity, specificity, and accuracy, reaching 84%, 86%, and 86% respectively. Conclusions: The radiogenomics of MIBC provides insight into features associated with cancer stages. Assisted with AI, the discriminative features can accurately stage MIBC. Source of Funding: Cedars-Sinai Cancer Internal Funds: Developmental Funds for Investigator Initiated Trials Using Advanced Imaging Methods.
First-in-class oral innate immune activator BXCL701 combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) variant: Randomized phase 2b trial.
Authors: Rahul Raj Aggarwal, Jingsong Zhang, Paul Monk, Xinhua Zhu, Dan Costin, Daniel P. Petrylak, Pascal Borderies, Rashmi Majali Deshpande, Amir Hafeez, Vincent J. O'Neill, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2023)

TPS5109 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 &amp; DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 &amp; IL-1ß, bridging innate &amp; adaptive immunity. BXCL701 + pembrolizumab evaluated in a Phase 2 study, in mCRPC patients with SCNC. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Final results of Phase 2a presented at ASCO GU 2023 (abstract #176) after enrollment of 28 evaluable SCNC patients. 7 (25%) patients achieved a composite response, primary endpoint of trial. In patients with measurable disease (n = 25), RECIST 1.1-defined partial response (PR) observed in 5 (20%) patients (4 confirmed PR + 1 uPR). Disease control rate (complete response + PR + stable disease) was 48% (12 patients). Median duration of response for both composite responses and RECIST-defined PRs was 6+ months as of data cutoff on 19-DEC-22. 6 / 34 patients (18%) in safety population experienced serious adverse events (SAEs) possibly related to BXCL701 or pembrolizumab, and 6 (18%) patients discontinued any drug due to an AE. No evidence found that BXCL701 potentiates immune-related AEs related to immune checkpoint inhibitors. DPP9 overexpression was identified as a potential predictive biomarker for BXCL701 response; biomarker evaluation is ongoing and additional findings will be presented at an upcoming medical meeting. Since SCNC cohort showed encouraging efficacy in Phase 2a, the Phase 2b portion of study was initiated to evaluate SCNC variant in a potential registrational randomized study. Methods: Patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, are randomized 2:1 to receive BXCL701 + pembrolizumab (n = 40) or BXCL701 monotherapy (n = 20). Patients are required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week Day 1) + BXCL701 or BXCL 701 alone (0.2 mg BID Days 1-7 with step-up to 0.3 mg BID Days 8-14, and 0.3 mg BID Days 1-14 of subsequent 21-day cycles). Primary endpoint is response rate defined by RECIST 1.1 criteria. Secondary objectives are ≥-50% decline in PSA from baseline, OS, duration of response, rPFS, and PSA PFS. Exploratory biomarkers and changes in relevant immune effector cells are also evaluated. Phase 2a activity threshold for accrual was met. ClinicalTrials.gov Identifier: NCT03910660. Clinical trial information: NCT03910660 .
Real-world study of treatment patterns and clinical outcomes in patients with metastatic non-small cell lung cancer (mNSCLC) post-approval of immunotherapy in the community oncology setting.
Authors: Alexander I. Spira, Beata Korytowsky, Sara Gao, Renard Dubois, Thomas Wilson, Andrew Osterland, Junxin Shi, Paul R. Conkling
Journal: Journal of Clinical Oncology (2023)

6629 Background: Clinical outcomes in patients with mNSCLC have improved post-approval of immunotherapy (IO). However, limited real-world data exists describing the evolution of treatment patterns and impact on outcomes in later lines of therapy (LOT). Here we describe the treatment landscape and outcomes of patients with mNSCLC without driver mutations within community oncology settings. Methods: This retrospective observational study included adult patients with mNSCLC who initiated first LOT (LOT1) for mNSCLC in the US Oncology Network from 1/1/2015 to 12/31/2020 (followed through 3/31/2022), using structured electronic health records. Patients who initiated LOT1 with a targeted therapy or EGFR/ALK/ROS1 inhibitor during any LOT were excluded. Second, third, and fourth LOT (LOT2, LOT3, LOT4) were assigned using start and stop dates. Treatment patterns up to LOT4 were summarized descriptively by period of treatment initiation (early-IO period: 2015–2017; post-IO period: 2018–2020). Overall survival (OS) and time to next treatment (TTNT) were assessed by LOT using Kaplan-Meier analysis. Results: Overall, 11,035 patients met study criteria, of which 3,835 (35%) patients initiated LOT2, 1,264 (11%) patients initiated LOT3, and 393 (4%) patients initiated LOT4 between 2015 and 2020, respectively. From 2015–2017 to 2018–2020, pembrolizumab plus platinum chemotherapy with pemetrexed or paclitaxel as LOT1 increased from 3% (n = 176) to 42% (n = 2,448), and pembrolizumab monotherapy increased from 9% (n = 465) to 26% (n = 1,518). In patients who initiated LOT2, IO followed by docetaxel ± ramucirumab increased from 1% (n = 15) to 15% (n = 295), whereas this sequence from LOT2 to LOT3 was used in 23% (n = 111) from 2015–2017 and 20% (n = 159) from 2018–2020. Median (95% CI) OS was 13.3 (12.6, 14.0) months vs. 14.7 (13.8, 15.3) months from initiation of LOT1 in 2015–2017 vs. 2018–2020, respectively (P = 0.187). Clinical outcomes by LOT and period of treatment initiation are presented as median (95% CI) in the table below. Conclusions: Understanding evolving treatment patterns in the community oncology setting is important for uncovering opportunities for mNSCLC treatment optimization. This descriptive study reveals the increasing use of mono- and combination IO followed by docetaxel ± ramucirumab in the community setting. Additionally, longer OS was noted in the post-IO period, suggesting possible extended benefits from earlier LOT. [Table: see text]
A step toward genomic equity: Mutational profiling of patients with myeloid neoplasm in the largest minority-serving hospital in metropolitan Chicago.
Authors: Maha AT Elsebaie, Ekrem Turk, Vaishali Deenadayalan, Khaldun Obeidat, Ahmad Nanaa, Maryam Zia, Noah W. Birch
Journal: Journal of Clinical Oncology (2023)

7037 Background: Information on genomic landscape of myeloid neoplasms comes from large studies of patients with predominantly European ancestry. Minority-serving hospitals offer unique opportunities to study ethnically diverse populations. Methods: In this retrospective study at the Stroger Hospital of Cook County, we included patients ≥18 years old with myeloid neoplasms or premalignant conditions who underwent mutational profiling via next generation sequencing (NGS). We utilized two commercially available myeloid panels: “ FoundationOneHeme” (406 gene panel) and “ Tempus” (648 gene panel) . Patient demographics were collected, including self-reported race/ethnicity. We compared data distribution using Kruskal-Wallis, Pearson’s χ2, or Fisher’s exact tests. Overall survival (OS) probabilities were compared using the log-rank test. Results: Ninety-four patients underwent NGS between 04/01/2020 and 12/31/2022, including 45 females (47.9%). 38 patients (40.4%) identified as Black, 28 (29.8%) as White, and 28 (29.8%) as Other (10.6% Asian, 9.6% Mexican/South American, and 9.6% undetermined). 30 patients (32%) identified as Hispanic and 64 (68%) as Non-Hispanic. Diagnoses included Acute myeloid leukemia (AML, 32%), Myelodysplastic syndromes (MDS, 13%), MDS/MPN overlap syndrome (7%), and Clonal Hematopoiesis of Indeterminate Potential (7%). Eighty-eight patients had at least one pathogenic variant and harbored 259 mutations in 74 genes. Commonly mutated genes were ASXL1 (23%), JAK2 (17%), DNMT3A (14%), and TET2 (13%).Non-White patients were more likely to have IDH2 mutations (5% Black vs. 0% White vs. vs. 14% Other races, p=0.011). Mutation count didn’t differ between racial p=0.525 or ethnic groups p=0.345. AML &amp; MDS patients were more likely to have TET2, RUNX1, TP53, and IDH2 mutations. In addition, 24% of AML &amp; MDS patients had mutated ASXL1. TET2, SRSF2, and RUNX1 mutations were common among MDS/MPN patients (Table). AML &amp; MDS patients had poor OS, but OS didn’t differ between racial/ethnic groups. Conclusions: Premalignant mutations (e.g., ASXL1, TET2) predominated in our patients and tended to co-occur, increasing the overall mutational burden. Non-White patients were more likely to have IDH2 mutations. Adverse markers were common among AML &amp; MDS patients, likely contributing to their dismal survival. Studies inclusive of ethnically diverse patients are needed to accurately translate genetic findings into clinical practice. This report from a large, minority-serving hospital represents a step toward promoting genomic and healthcare equity. [Table: see text]
Frequency of fluoropyrimidine-related toxicity in patients with colon cancer from a Mexican oncology center.
Authors: Francisco J Alvarado Villarreal, Maria Lourdes Garza-Rodriguez, Azael Elian Garibay-Villegas, Nicole Treviño-Martínez, Fernando Alcorta-Nuñez, Carlos Horacio Burciaga Flores, Oscar Vidal-Gutiérrez, Alan Burguete-Torres, Diana Cristina Pérez-Ibave
Journal: Journal of Clinical Oncology (2023)

e15616 Background: Fluoropyrimidines are chemotherapeutic agents used in various types of cancer such as colorectal, breast, gastric, etc. Approximately 30% of patients treated with fluoropyrimidines present severe toxicity, which can lead to death in around 1% of them. Reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD) can cause severe fluoropyrimidine-related toxicity. The objective of this study was to identify the frequency of fluoropyrimidine-related toxicity in patients treated at an oncology center from Northeast Mexico. Methods: Retrospective and observational study of patients treated at the Centro Universitario contra el Cáncer (CUCC) in Monterrey, Mexico. Patients older than 18 years with a diagnosis of colon cancer who were treated during 2021 with the diagnosis of colon and considered candidates for fluoropyrimidine-based chemotherapy (5-FU, capecitabine) were included. Pregnant patients were excluded. None of them had a DPYD testing performed. Results: We analyzed 88 patients, of whom 51 (58%) were men, 6 (7%) in stage I, 16 (18%) in stage II, 31 (35%) in stage III, and 35 (40%) in stage IV. The mean age was 59 years, 15 (17%) of them had a PS&gt;2, overall, 94% of patients received fluoropyrimidine-based CT, presenting up to 47 (57%) of toxicities, 26 (32%) in G1, 11 (13%) in G2, and 10 (12%) in G3; no G &gt; 4 toxicities were documented. There were 7 patients (9%) that required CT discontinuation due to toxicity at some point during their treatment (see Table 1). In the subgroup of patients in stage IV, 8 (24%) had PS&gt;2, and 6 (18%) of them had some mutational panel. Conclusions: This is one of the few descriptive studies of toxicities in a population from northeastern Mexico undergoing treatment with fluoropyrimidine-based CT, in which up to 9% of the patients discontinue treatment due to toxicity. Our findings evidence a high percentage of patients with fluoropyrimidine-related toxicity. DPYD testing has not been widely adopted in most oncology centers in Mexico, mostly because of the limited access to genome sequencing. Genetic studies in this population could identify poor metabolizers patients with a high risk of toxicity before starting treatment. [Table: see text]
Prognostic risk stratification of low-grade serous ovarian cancer: Model development and validation based on machine learning algorithm.
Authors: Zhongshao Chen, Kai Zhang, Ran Chu, Kun Song
Journal: Journal of Clinical Oncology (2023)

e17569 Background: Low-grade serous ovarian cancer (LGSOC) is a rare ovarian tumor that lacks a prognostic prediction model. We attempted to construct a clinical nomogram to predict the recurrence and survival of patients with LGSOC. Methods: A multicenter clinical cohort of 199 patients with pathologically confirmed LGSOC was constructed. The predictive model factors were recurrence and survival related clinical factors, which were determined by univariate and multivariate COX regression analysis. The area under receiver operating characteristic curve (AUC), and calibration curve were used to assess the accuracy and discrimination of the nomogram. The concordance index(C-index), net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to evaluate the efficacy of nomogram and FIGO staging in predicting recurrence and survival. Results: A total of 155 patients were included, and four independent prognostic factors were identified to construct the prediction model. The AUC ( &gt; 0.8) showed satisfactory discriminative ability of the nomogram, and the calibration curve showed good agreement between the predicted outcome and the actual outcome. The C-index (PFS: 0.791 vs 0.693; OS: 0.808 vs 0.674), NRI values (0.181 for 3-year and 0.278 for 5-year OS prediction) and IDI values(0.141 for 3-year and 0.147 for 5-year OS prediction, 0.089 for 3-year and 0.079 for 5-year PFS prediction) results showed that nomogram performed better than FIGO staging in predicting prognosis(p &lt; 0.01). Conclusions: We constructed and validated clinical nomogram to individually predict recurrence and survival outcomes in patients with LGSOC, which can help evaluate the prognosis of patients.
ExoLuminate: An observational registry study for detection of pancreatic adenocarcinoma (PDAC) in high-risk or clinically suspicious patients.
Authors: Harmeet Dhani, Juan Pablo Hinestrosa, Jesus Izaguirre Carbonell, Heath Balcer, Razelle Kurzrock, Paul R. Billings
Journal: Journal of Clinical Oncology (2023)

TPS4203 Background: The detection of pancreatic ductal adenocarcinoma (PDAC) at early-stages is critical to improving patient survival. However, the lack of a clinically useful biomarker assay poses a challenge for earlier detection. A liquid biopsy test (ExoVita Pancreas) which uses extracellular vesicles (EV) protein biomarkers has been developed for detection of PDAC. In a previous case-control study of n=715 (75 cases of PDAC Stage I and II, 640 controls), the EV-protein biomarker assay yielded a sensitivity of 96.0% and specificity of 91.1%. By optimizing the assay for high sensitivity, we aim to generate evidence for earlier detection of PDAC in high-risk and clinically suspicious patients in the hope of impacting PDAC patient diagnostic journeys. Methods: ExoLuminate is a prospective, multi-center, observational registry study to demonstrate that early detection of PDAC using ExoVita is non-inferior to current standard of care methods of surveillance. The study duration will be 36 months (24-month accrual, 12-month follow-up), with a minimum of 1000 subjects to be enrolled between two cohorts as described below. The first cohort enriches for “high-risk” individuals without a cancer suspicion or diagnosis including those with intraductal papillary mucinous neoplasms (IPMNs), personal or family history of pancreatitis, family member(s) who have at least one first-degree relative affected by pancreatic cancer, patients over 50 years of age with new-onset diabetes (NOD), and germline mutations known to be associated with PDAC. The second cohort includes patients with clinical findings suspicious for early-stage PDAC or those with biopsy-proven PDAC. Patients enrolled in the study will have their blood obtained at six-month intervals. The performance of ExoVita liquid biopsy will be compared to standard-of-care imaging and biomarkers such as CA19-9. Through this registry, which began enrollment in December 2022 and is open for accrual (NCT0562552), we aim to demonstrate the clinical utility of a novel liquid biopsy based on detection of EV-derived biomarkers for early diagnosis of PDAC which can provide credence to a new paradigm in early detection to improve patient outcomes. Clinical trial information: NCT0562552 .
Genome-wide aneuploidy detected in circulating cell-free DNA of patients with metastatic urothelial cancer as a predictive biomarker of response to pembrolizumab.
Authors: Youssra Salhi, Maud Rijnders, Pauline Mendelaar, Vania de Weert, Corine Beaufort, R Head, Hans M. Westgeest, Jens Voortman, Maureen J.B. Aarts, John W.M. Martens, Astrid Aplonia Maria Van Der Veldt, Ronald De Wit, Saskia M Wilting, Debbie Robbrecht
Journal: Journal of Clinical Oncology (2023)

4584 Background: Pembrolizumab is the standard of care second-line treatment of metastatic urothelial cancer patients. However, success rates are low and there is risk for significant toxicity. Therefore, reliable biomarkers to select patients who will or will not benefit from pembrolizumab are urgently needed. An earlier study showed that a high aneuploidy score (i.e. Z-score ≥ 5) at baseline in cell free DNA (cfDNA), based on the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), associated with poor response to pembrolizumab. However, a low aneuploidy score (Z-score &lt; 5) at baseline was not discriminative. The aim of this study was to evaluate early during treatment (after the first cycle pembrolizumab), whether the cfDNA based mFast-SeqS aneuploidy scores can discriminate patients with expected benefit from therapy from those who will not benefit. Methods: The mFast-SeqS to assess aneuploidy was performed on blood samples collected from 74 patients with metastatic urothelial cancer (mUC) at baseline and after cycle 1 of pembrolizumab. Responders were defined as patients with stable disease (SD) or partial/complete response (PR, CR) according to RECIST v1.1. and continued treatment beyond 6 months from initiation of pembrolizumab. Non-responders did not fulfil these criteria. Results: Paired samples were available in 60 out of 74 patients. At baseline 25% (n=15) of patients had a high aneuploidy score and 75% (n=45) had a low aneuploidy score. Two patients (13%) with a high baseline score were responders and 13 (87%) were non-responders. In all responders, there was a marked decrease in aneuploidy score after one cycle of pembrolizumab (p=0.005), irrespective of their baseline score. About half of patients (47%) with a low baseline score were non-responders and in those patients there was a significant increase of the aneuploidy score post cycle 1, when compared to the responders (p=0.039). Conclusions: The aneuploidy score based on mFast-SeqS may stratify mUC patients for expected lack of benefit early during treatment (after 1 cycle) with second line pembrolizumab, providing an opportunity to switch treatment and to spare patients from potential unnecessary toxicity. Clinical trial information: NCT03263039 .